Cancer is a devastating disease and remains a significant cause of mortality and morbidity in both developed and developing countries. Although there are large number of drugs that can be used for the treatment of cancer, the problem is selective and specific killing of cancerous cells without harming the normal cells. There are some biological barriers to potential drug delivery in cancer cells like hepatic, renal, abnormal vasculature, dense extracellular matrix, and high interstitial fluid pressure. The physicochemical characteristics of nanoparticles (NPs) such as size, shape, and surface charge may also have significant effects on tumor penetration. NPs coated with drug can be used to overcome these biological barriers to enhance targeted delivery. This literature survey encompasses the biological barriers to potential drug delivery in cancer cells, elaborate on designing strategies to enhance NPs penetration and distribution inside the tumor interstitium. Scientists are now doing great efforts to design next-generation of nanomedicines (NMs) that need to be better targeted with high specificity and efficacy to kill cancer cells. These challenges need to be overcome through collaborations among academia, pharmaceutical industries, and regulatory agencies to eradicate this global menace. Furthermore, this review article has critically discussed the recent developments, controversies, challenges, emerging concepts, and future perspectives in cancer NMs.